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Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes.
Neurobiol Dis. 2007 Jul; 27(1):102-7.ND

Abstract

gamma-Secretase is a protease complex, which catalyzes the final of two subsequent cleavages of the beta-amyloid precursor protein (APP) to release the amyloid-beta peptide (Abeta) implicated in Alzheimer's disease (AD) pathogenesis. In human cells, six gamma-secretase complexes exist, which are composed of either presenilin (PS) 1 or 2, the catalytic subunit, nicastrin, PEN-2, and either APH-1a (as S or L splice variants) or its homolog APH-1b. It is not known whether and how different APH-1 species contribute to the pathogenic activity of gamma-secretase complexes with familial AD (FAD)-associated mutant PS. Here we show that all known gamma-secretase complexes are active in APP processing and that all combinations of APH-1 variants with either FAD mutant PS1 or PS2 support pathogenic Abeta(42) production. Since our data suggest that pathogenic gamma-secretase activity cannot be attributed to a discrete gamma-secretase complex, we propose that all gamma-secretase complexes have to be explored and evaluated for their potential as AD drug target.

Authors+Show Affiliations

Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, Schillerstr 44, Munich, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17560791

Citation

Shirotani, Keiro, et al. "Pathological Activity of Familial Alzheimer's Disease-associated Mutant Presenilin Can Be Executed By Six Different Gamma-secretase Complexes." Neurobiology of Disease, vol. 27, no. 1, 2007, pp. 102-7.
Shirotani K, Tomioka M, Kremmer E, et al. Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes. Neurobiol Dis. 2007;27(1):102-7.
Shirotani, K., Tomioka, M., Kremmer, E., Haass, C., & Steiner, H. (2007). Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes. Neurobiology of Disease, 27(1), 102-7.
Shirotani K, et al. Pathological Activity of Familial Alzheimer's Disease-associated Mutant Presenilin Can Be Executed By Six Different Gamma-secretase Complexes. Neurobiol Dis. 2007;27(1):102-7. PubMed PMID: 17560791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes. AU - Shirotani,Keiro, AU - Tomioka,Masanori, AU - Kremmer,Elisabeth, AU - Haass,Christian, AU - Steiner,Harald, Y1 - 2007/05/06/ PY - 2007/01/12/received PY - 2007/04/03/revised PY - 2007/04/27/accepted PY - 2007/6/15/pubmed PY - 2007/9/7/medline PY - 2007/6/15/entrez SP - 102 EP - 7 JF - Neurobiology of disease JO - Neurobiol Dis VL - 27 IS - 1 N2 - gamma-Secretase is a protease complex, which catalyzes the final of two subsequent cleavages of the beta-amyloid precursor protein (APP) to release the amyloid-beta peptide (Abeta) implicated in Alzheimer's disease (AD) pathogenesis. In human cells, six gamma-secretase complexes exist, which are composed of either presenilin (PS) 1 or 2, the catalytic subunit, nicastrin, PEN-2, and either APH-1a (as S or L splice variants) or its homolog APH-1b. It is not known whether and how different APH-1 species contribute to the pathogenic activity of gamma-secretase complexes with familial AD (FAD)-associated mutant PS. Here we show that all known gamma-secretase complexes are active in APP processing and that all combinations of APH-1 variants with either FAD mutant PS1 or PS2 support pathogenic Abeta(42) production. Since our data suggest that pathogenic gamma-secretase activity cannot be attributed to a discrete gamma-secretase complex, we propose that all gamma-secretase complexes have to be explored and evaluated for their potential as AD drug target. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/17560791/Pathological_activity_of_familial_Alzheimer's_disease_associated_mutant_presenilin_can_be_executed_by_six_different_gamma_secretase_complexes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(07)00095-2 DB - PRIME DP - Unbound Medicine ER -